1. Field of the Invention
The present invention relates generally to the field of neurobiology. More specifically, the present invention relates to compounds, specifically phenylglycine derivatives, that inhibit the release of toxic levels of glutamate from brain tumor cells.
2. Description of the Related Art
L-glutamate is an important nutritional amino acid involved in a number of biochemical pathways. Glutamate is also the main excitatory amino acid transmitter in the mammalian central nervous system. Extracellular glutamate concentrations are normally maintained at low micromolar levels to assure proper synaptic function and to prevent excitotoxic injury of neurons (1,2). This is accomplished through the activity of several Na.sup.+ -dependent glutamate transporters expressed by neurons and astrocytes. Of the 5 glutamate transporter subtypes cloned (3-7), two, namely GLAST and GLT-1, appear to be predominantly located on glial cells (8,9).
It is believed that astrocytes, which comprise a large portion of the total cell population in the mammalian nervous system, are particularly important in maintaining glutamate homeostasis (10-13), since their processes closely encapsulate synapses and they are invulnerable to glutamate challenge. Like neurons, astrocytes maintain a large transmembrane glutamate gradient, with intracellular glutamate concentrations of 2-10 mM (14-16), while the [Glu].sub.o is approximately 1 .mu.M (2,17). Since astrocytic glutamate transport is electrogenic and uses the transmembrane electrochemical gradient for Na.sup.+, K.sup.+ and H.sup.+ (18,19), severe disruption of these gradients, or membrane depolarization under conditions of energy failure (ischemia, hypoglycemia), can lead to glutamate release from astrocytes by reversal of glutamate transport (20-22).
Unlike neurons, glial cells retain the ability to proliferate post-natally. Uncontrolled, cancerous proliferation of glial cells results in primary brain tumors, collectively termed gliomas. The vast majority of gliomas originate through the neoplastic transformation of astrocytes. Astrocyte-derived tumors often develop over the course of many months to years, beginning as slowly growing low-grade astrocytomas and progressing towards more aggressive astrocytomas that eventually can give rise to gliobastoma multiforme, the most aggressive glial-derived tumors.
The cellular and functional changes that accompany the malignant transformation of astrocytes is poorly understood. As in other cancers, a number of genetic alterations precede the malignant phenotype and are conspicuous features, including upregulation of growth factor receptors, and changes in extracellular matrix molecules (24) and focal adhesion sites (25). Neovasularization and focal necrosis are also consistent features of high grade gliomas (26). It is not clear if or how the growing tumor mass causes neuronal cell death along the growing tumor margins. However, epileptic seizures, as an indicator of compromised neural function, are commonly associated with brain tumors (27).
It is shown herein that glioma cells are impaired in their ability to remove glutamate from the extracellular space, and in addition, actively release glutamate at concentrations that can induce widespread neurotoxicity. This finding suggests that tumors may actively induce neuronal death at the growing tumor margins and that glutamate release by tumors may contribute to seizure activity arising from peritumoral brain regions.
The prior art is deficient in compositions and methods that inhibit the toxic release of glutamate from brain tumor cells. The present invention fulfills this long-standing need and desire in the art.